Gene modification may benefit human neurological disorders such as Alzheimer's disease (AD). Grafting cells to the brain that are genetically modified to secrete a specific molecule potentially permits chronic, well- tolerated and regionally specific substance delivery. In AD, this approach could be utilized to administer trophic agents such as nerve growth factor (NGF) to the brain to retard cholinergic neuronal degeneration, or to replenish neurotransmitter deficiencies including losses of acetylcholine, serotonin, norepinephrine, or peptides. This approach might also be utilized to replenish or block substances that potentially contribute to AD development, such as neurofilament or beta-amyloid protein abnormalities. This project will examine whether gene therapy can prevent cholinergic neuronal degeneration in the adult primate brain and restore morphological and/or behavioral deficits that occur in aged primates. Although deficiencies of multiple transmitter systems occur in AD, cholinergic neuronal degeneration is targeted in this proposal for several reasons: 1) Disturbances of cholinergic function in both animals and in human volunteers result in memory loss, a cardinal feature of AD. 2) Both the clinical severity of AD and the severity of a pathological marker of the disease, senile plaques, correlate with losses of cholinergic neuronal markers. 3) Degeneration of cholinergic neurons in the adult brain can be prevented by NGF infusions, providing a useful model for degenerative disorders. The goals of this project are to transduce primary primate fibroblasts with the cDNAs for NGF or ChAT (the biosynthetic enzyme for acetylcholine), then characterize the survival and expression of these transgenes in vitro and in vivo. The synthesis, secretion and biological activity of transgene products will be assessed. Finally, the extent to which transgeneic cells can induce neuronal repair and/or functional recovery in model systems of cholinergic loss, aging, and AD will be assessed.